A processable rubber stock is produced by the preparation of a silica-filled, vulcanized elastomeric compound comprising mixing an elastomer with an amorphous silica filler, from 0 to less than about 1% by weight based on said silica filter of bis[3-triethoxysilyl)propyl]tetrasulfide, an alkylalkoxysilane and a cure agent. A further processing aid comprising at least one of an ester of a fatty acid or an ester of a polyol is preferred. The elastomer is preferably a diene monomer homopolymer or a copolymer of at least one diene and at least one monovinyl aromatic monomer. By effecting vulcanization, a vulcanized elastomeric compound is produced containing good physical properties for use as tread stock for a pneumatic tire.

The subject invention relates to the processing and vulcanization of diene polymer and copolymer elastomer containing rubber stocks. More specifically, the present invention relates to the processing and vulcanization of diene polymer and copolymer elastomer-containing, silica-filled rubber stocks using a mixture of silanes as processing aids.
In the art it is desirable to produce elastomeric compounds exhibiting reduced hysteresis when properly compounded with other ingredients such as reinforcing agents, followed by vulcanization. Such elastomers, when compounded, fabricated and vulcanized into components for constructing articles such as tires, power belts, and the like, will manifest properties of increased rebound, decreased rolling resistance and less heat-build up when subjected to mechanical stress during normal use.
The hysteresis of an elastomer refers to the difference between the energy applied to deform an article made from the elastomer and the energy released as the elastomer returns to its initial, undeformed state. In pneumatic tires, lowered hysteresis properties are associated with reduced rolling resistance and heat build-up during operation of the tire. These properties, in turn, result in lowered fuel consumption of vehicles using such tires.
In such contexts, the property of lowered hysteresis of compounded, vulcanizable elastomer compositions is particularly significant. Examples of such compounded elastomer systems are known to the art and are comprised of at least one elastomer (that is, a natural or synthetic polymer exhibiting elastomeric properties, such as a rubber), a reinforcing filler agent (such as finely divided carbon black, thermal black, or mineral fillers such as clay and the like) and a vulcanizing system such as sulfur-containing vulcanizing (that is, curing) system.
Previous attempts at preparing readily processable, vulcanizable, silica-filled rubber stocks containing natural rubber or diene polymer and copolymer elastomers have focused upon the sequence of adding ingredients during mixing (Bomal, et al., Influence of Mixing procedures on the Properties of a Silica Reiniforced Agricultural Tire Tread, May 1992), the addition of de-agglomeration agents such as zinc methacrylate and zinc octoate, or SBR-silica coupling agents such as mercapto propyl trimethoxy silane (Hewitt, Processing Technology of Silica Reinforced SBR, Elastomerics, pp 33-37, March 1981), and the use of bis[3-(triethoxysilyl)propyl]tetrasulfide (Si69) processing aid (Degussa, PPG).
The use of Si69 processing aid in the formulation of silica-filled rubber stocks has been successful, but generally requires a large amount of the additive, such as 10% by weight based on the weight of silica, in order to be effective.
Precipitated silica has been increasingly used as a reinforcing particulate filler in carbon black-filled rubber components of tires and mechanical goods. Silica- loaded rubber stocks, however, exhibit relatively poor processability.
The present invention provides a mixture of silanes for use as processing aids for silica-filled rubber stocks, which greatly improve the processability and properties of the formulations and resulting vulcanized product.
It is therefore an object of the present invention to provide rubber stock processing aids which improve the processability of formulations of diene polymer elastomers with silica-filler.
It is another object of the present invention to provide a method for reducing the viscosity of silica-filled elastomeric vulcanizable compounds.
It is another object of the present invention to provide a method for enhancing the processability of silica-filled elastomeric vulcanizable compounds.
It is another object of the present invention to provide vulcanizable silica-filled elastomeric compounds having enhanced physical properties.
The foregoing objects, together with the advantages thereof over the existing art, which shall become apparent from the specification which follows, are accomplished by the invention as hereinafter described and claimed.
The present invention provides a process for the preparation of a silica-filled, vulcanized elastomeric compound comprising: mixing an elastomer with an amorphous silica filler, from 0 to less than about 1% by weight based on said silica filler of bis[3- (triethoxysilyl)propyl]tetrasulfide, an alkylalkoxysilane and a cure agent; and, effecting vulcanization. Preferably, the elastomer is a diene monomer homopolymer or a copolymer of a diene monomer and a monovinyl aromatic monomer.
The present invention further provides a vulcanizable silica-filled compound comprising an elastomer, a silica filler, from 0 to less than about 1% by weight based on said silica filler of bis[3-(triethoxysilyl)propyl]tetrasulfide (Si69), an alkylalkoxysilane and a cure agent. Preferably, the elastomer is styrene butadiene rubber, optionally containing a carbon black filler. The compound is more readily processable during mixing, due to the use of the mixture of silane processing aids.
The present invention further provides a pneumatic tire comprising tread stock vulcanized from the inventive vulcanizable silica-filled compound.
In general, the present invention provides a means to reduce the level of Si69 needed to obtain good physical properties in a cured rubber stock containing silica as a filler. In addition, the present invention further provides maintenance of the processability of the compounded stock, as measured by Mooney viscosity, at the same level as achieved with high levels of Si69.
The present invention utilizes the presence of an alkylalkoxysilane as a silica hydrophobating agent, such that minimal amounts of Si69 are needed to obtain good processability, and yet still give good physical properties. According to the invention, therefore, a less costly silane can be substituted for the majority or all of the Si69 that would be normally used without any loss of processability or properties. Additionally, remilling can be eliminated, and the cure of the rubber stock is not dependent on the high sulfur level present in the Si69.
The silica-hydrophobating agents useful according to the present invention include those alkylalkoxysilanes of the formula (R1)2Si(OR2)2 or R1Si(OR2)3, wherein the alkoxy groups are the same or are different; each R1 independently comprising C1 to about C18 aliphatic, about C6 to about C12 cyclo-aliphatic, or about C6 to about C18 aromatic, preferably C1 to about C10 aliphatic, about C6 to about C10 cyclo-aliphatic, or about C6 to about C12 aromatic; and each R2 independently containing from one to about 6 carbon atoms. Representative examples include octyltriethoxy silane, octyltrimethyloxy silane, (3-glycidoxypropyl)trimethoxy silane, (3- octyltrimethoxy silane, hexyltrimethoxy silane, ethytrimethyoxy silane, propyltriethoxy silane, phenyltrimethoxy silane, cyclohexyltrimethoxy silane, cyclohexyltriethoxy silane, dimethyldimethoxy silane, i-butyltriethoxy silane, and the like. Of these, octyltriethoxysilane is preferred.
According to the present invention, polymerized elastomer is compounded in the rubber stock, e.g., polybutadiene, polyisoprene and the like, and copolymers thereof with monovinyl aromatics such as styrene, alpha methyl styrene and the like, or trienes such as myrcene. Thus, the elastomers include diene homopolymers, A, and copolymers thereof with monovinyl aromatic polymers, B. Exemplary diene homopolymers are those prepared from diolefin monomers having from 4 to about 12 carbon atoms. Exemplary vinyl aromatic polymers are those prepared from monomers having from 8 to about 20 carbon atoms. Examples of conjugated diene monomers and the like useful in the present invention include 1,3-butadiene, isoprene, 1,3-pentadiene, 2,3-dimethyl-1,3-butadiene and 1,3-hexadiene, and aromatic vinyl monomers include styrene, a-methylstyrene, p-methylstyrene, vinyltoluenes and vinylnaphthalenes. The conjugated diene monomer and aromatic vinyl monomer are normally used at the weight ratios of about 90:10 to about 55:45, preferably about 80:20 to about 65:35.
Preferred elastomers include diene homopolymers such as polybutadiene and polyisoprene and copolymers such as styrene butadiene rubber (SBR). Copolymers can comprise from about 99 to 20 percent by weight of diene units and from about 1 to about 80 percent by weight of monovinyl aromatic or triene units, totaling 100 percent. The polymers and copolymers of the present invention may have the diene portion with a 1,2-microstructure contents ranging from about 10 to about 80 percent, with the preferred polymers or copolymers having 1,2-microstructure contents of from about 25 to 65 percent. The molecular weight of the polymer that is produced according to the present invention, is preferably such that a proton-quenched sample will exhibit a gum Mooney viscosity (ML4/212xc2x0 F.) of from about 2 to about 150. The copolymers are preferably random copolymers which result from simultaneous copolymerization of the monomers, as is known in the art. Also included are nonfunctionalized cis-polybutadiene, ethylene-propylene-diene monomer (EPDM), emulsion SBR and natural rubber.
Initiators known in the art such as an organolithium initiator, preferably an alkyllithium initiator, can be employed to prepare the elastomer. More particularly, the initiators used in the present invention include N-lithio-hexamethyleneimine, organolithium compounds such as n-butyllithium, tributyltin lithium, dialkylaminolithium compounds such as dimethylaminolithium, diethylaminolithium, dipropylaminolithium, dibutylaminolithium and the like, dialkylaminoalkyllithium compounds such as diethylaminopropyllithium and the like, and trialkyl stanyl lithium, wherein the alkyl group contains 1 to about 12 carbon atoms, preferably I to about 4 carbon atoms.
Polymerization is usually conducted in a conventional solvent for anionic polymerizations such as the various cyclic and acyclic hexanes, heptanes, octanes, pentanes, their alkylated derivatives, and mixtures thereof. Other techniques for polymerization, such as semi-batch and continuous polymerization may be employed. In order to promote randomization in copolymerization and to increase vinyl content, a coordinator may optionally be added to the polymerization ingredients. Amounts range between 0 to 90 or more equivalents per equivalent of lithium. The amount depends upon the amount of vinyl desired, the level of styrene employed and the temperature of the polymerizations, as well as the nature of the specific polar coordinator employed.
Compounds useful as coordinators are organic and include those having an oxygen or nitrogen hetero-atom and a non-bonded pair of electrons. Examples include dialkyl ethers of mono and oligo alkylene glycols; xe2x80x9ccrownxe2x80x9d ethers; tertiary amines such as tetramethylethylene diamine (TMEDA); THF; THF oligomers; linear and cyclic oligomeric oxolanyl alkanes, such as 2-2xe2x80x2-di(tetrahydrofuryl) propane, di-piperidyl ethane, hexamethylphosphoramide, N-Nxe2x80x2-dimethylpiperazine, diazabicyclooctane, diethyl ether, tributylamine and the like. Details of linear and cyclic oligomeric oxolanyl coordinators can be found in U.S. Pat. No. 4,429,091, owned by the Assignee of record, the subject matter of which is incorporated herein by reference.
Polymerization is usually begun by charging a blend of the monomer(s) and solvent to a suitable reaction vessel, followed by the addition of the coordinator and the initiator solution previously described. Alternatively, the monomer and coordinator can be added to the initiator. The procedure is carried out under anhydrous, anaerobic, conditions. The reactants are heated to a temperature of from about 10xc2x0 to 150xc2x0 C. and are agitated for about 0.1 to 24 hours. After polymerization is complete, the product is removed from the heat and terminated in one or more ways.
To terminate the polymerization, a terminating agent, coupling agent or linking agent may be employed, all of these agents being collectively referred to herein as xe2x80x9cterminating agentsxe2x80x9d. Certain of these agents may provide the resulting polymer with a multifunctionality. That is, the polymers initiated according to the present invention, carry at least one amine functional group as discussed hereinabove, and may also carry a second functional group selected and derived from the group consisting of terminating agents, coupling agents and linking agents.
Examples of terminating agents according to the present invention include those commonly employed in the art, including hydrogen, water, steam, an alcohol such as isopropanol, 1,3-dimethyl-2-imidazolidinone (DMI), carbodiimides, N-methylpyrrolidine, cyclic amides, cyclic ureas, isocyanates, Schiff bases, 4,4xe2x80x2-bis(diethylamino) benzophenone, and the like. Other useful terminating agents may include those of the structural formula (R1)a ZXb, wherein Z is tin or silicon. It is preferred that Z is tin. R1 is an alkyl having from about 1 to about 20 carbon atoms; a cycloalkyl having from about 3 to about 20 carbon atoms; an aryl having from about 6 to about 20 carbon atoms; or, an aralkyl having from about 7 to about 20 carbon atoms. For example, R1 may include methyl, ethyl, n-butyl, neophyl, phenyl, cyclohexyl or the like. X is a halogen, such as chlorine or bromine, or an alkoxy (xe2x80x94OR1), xe2x80x9caxe2x80x9d is from 0 to 3, and xe2x80x9cbxe2x80x9d is from about 1 to 4; where a+b=4. Examples of such terminating agents include tin tetrachloride, (R1)3SnCl, (R1)2SnCl2, R1SnCl3, and R1SiCl3 as well as methyltriphenoxysilane (MeSi(OPh3)).
The terminating agent is added to the reaction vessel, and the vessel is agitated for about 1 to about 1000 minutes. As a result, an elastomer is produced having an even greater affinity for silica compounding materials, and hence, even further reduced hysteresis. Additional examples of terminating agents include those found in U.S. Pat. No. 4,616,069 which is herein incorporated by reference. It is to be understood that practice of the present invention is not limited solely to these terminators inasmuch as other compounds that are reactive with the polymer bound lithium moiety can be selected to provide a desired functional group.
Quenching is usually conducted by stirring the polymer and quenching agent for about 0.05 to about 2 hours at temperatures of from about 30xc2x0 to 120xc2x0 C. to ensure complete reaction. Polymers terminated with a functional group as discussed hereinabove, can be subsequently quenched with alcohol or other quenching agents as described hereinabove.
Lastly, the solvent is removed from the polymer by conventional techniques such as drum drying, extruder drying, vacuum drying or the like, which may be combined with coagulation with water, alcohol or steam, thermal desolventization, or any other suitable method. If coagulation with water or steam is used, oven drying may be desirable.
The elastomeric polymers can be utilized as 100 parts of the rubber in the treadstock compound or, they can be blended with any conventionally employed treadstock rubber which includes natural rubber, synthetic rubber and blends thereof. Such rubbers are well known to those skilled in the art and include synthetic polyisoprene rubber, styrene/butadiene rubber (SBR), polybutadiene, butyl rubber, Neoprene, ethylene/propylene rubber, ethylene/propylene/diene rubber (EPDM), acrylonitrile/butadiene rubber (NBR), silicone rubber, the fluoroelastomers, ethylene acrylic rubber, ethylene vinyl acetate copolymer (EVA), epichlorohydrin rubbers, chlorinated polyethylene rubbers, chlorosulfonated polyethylene rubbers, hydrogenated nitrile rubber, tetrafluoroethylene/propylene rubber and the like. When the polymers discussed hereinabove are blended with conventional rubbers, the amounts can vary widely with a range comprising about 5 to about 99 percent by weight of the total rubber. It is to be appreciated that the minimum amount will depend primarily upon the degree of reduced hysteresis that is desired.
According to the present invention, amorphous silica (silicon dioxide) is utilized as a filler for the diene polymer or copolymer elastomer-containing vulcanizable compound. Silicas are generally classed as wet-process, hydrated silicas because they are produced by a chemical reaction in water, from which they are precipitated as ultrafine, spherical particles.
These primary particles strongly associate into aggregates, which in turn combine less strongly into agglomerates. The surface area, as measured by the BET method gives the best measure of the reinforcing character of different silicas. For silicas of interest for the present invention, the surface area should be about 32 to about 400 m2/g, with the range of about 100 to about 250 m2/g being preferred, and the range of about 150 to about 220 m2/g being most preferred. The pH of the silica filler is generally about 5.5 to about 7 or slightly over, preferably about 5.5 to about 6.8.
Silica can be employed in the amount of about 1 part to about 100 parts per 100 parts of polymer (phr), preferably in an amount from about 5 to about 80 phr. The useful upper range is limited by the high viscosity imparted by fillers of this type. Some of the commercially available silicas which may be used include: Hi-Sil(copyright) 215, Hi-Sil(copyright) 233, and Hi-Sil(copyright) 190, all produced by PPG Industries. Also, a number of useful commercial grades of different silicas are available from De Gussa Corporation, Rhone Poulenc, and J.M. Huber Corporation.
The polymers can be compounded with all forms of carbon black in amounts ranging from about 2 to about 50 parts by weight, per 100 parts of rubber (phr), with about 5 to about 40 phr being preferred. The carbon blacks may include any of the commonly available, commercially-produced carbon blacks but those having a surface area (EMSA) of at least 20 m2gram and more preferably at least 35 m2/gram up to 200 m2/gram or higher are preferred. Surface area values used in this application are those determined by ASTM test D-1765 using the cetyltrimethyl-ammonium bromide (CTAB) technique. Among the useful carbon blacks are furnace black, channel blacks and lamp blacks. More specifically, examples of the carbon blacks include super abrasion furnace (SAF) blacks, high abrasion furnace (HAF) blacks, fast extrusion furnace (FEF) blacks, fine furnace (FF) blacks, intermediate super abrasion furnace (ISAF) blacks, semi-reinforcing furnace (SRF) blacks, medium processing channel blacks, hard processing channel blacks and conducting channel blacks. Other carbon blacks which may be utilized include acetylene blacks. Mixtures of two or more of the above blacks can be used in preparing the carbon black products of the invention. Typical values for surface areas of usable carbon blacks are summarized in the Table I hereinbelow.
The carbon blacks utilized in the preparation of the rubber compounds of the invention may be in pelletized form or an unpelletized flocculent mass. Preferably, for more uniform mixing, unpelletized carbon black is preferred.
The reinforced rubber compounds can be cured in a conventional manner with known vulcanizing agents at about 0.2 to about 5 phr. For example, sulfur or peroxide-based curing systems may be employed. For a general disclosure of suitable vulcanizing agents one can refer to Kirk-Othmer, Encyclopedia of Chemical Technology, 3rd ed., Wiley Interscience, N.Y. 1982, Vol. 20, pp. 365-468, particularly 359xe2x80x9cVulcanization Agents and Auxiliary Materialsxe2x80x9d pp. 390-402. Vulcanizing agents can be used alone or in combination.
Vulcanizable elastomeric compositions of the invention can be prepared by compounding or mixing the elastomeric polymer with silica, optionally carbon black, the silica-hydrophobating agent according to the present invention, a minimal amount of Si69, and other conventional rubber additives including for example, fillers, plasticizers, antioxidants, curing agents and the like, using standard rubber mixing equipment and procedures.

Processability of silica-filled rubber stocks


A dosage form which rapidly disintegrates in the mouth and forms a viscous slurry of either microcapsules or a powder is described. The rapidly disintegrating dosage form is meant for direct oral administration by placing a tablet or capsule in the mouth of a patient. Upon disintegration, a viscosity of the resulting slurry increases so as to form an organoleptically pleasant viscous material which retards the spread of insoluble materials including the drug.

The invention relates to the fields of pharmacy and medicine and to orally disintegrable dosage forms for the delivery of sustained or extended release microcapsules and/or prompt release coated or non-coated drug particles.
There are many formulations known for administering extended or sustained release forms of various medicines. A common method involves the administration of microencapsulated or otherwise coated drug substances. Coating can be errodable or disintegrable or it can be selectively porous, effectively controlling the release or diffusion of the drug contained within it. The administration of such particles is, not without complexity. Tableting may crush the particles interfering with their otherwise preplanned drug administration rate. Suspension or liquid vehicles may be desirable, but the potential for leakage of the drug is increased. Capsules containing granules or beads may be an alternative. However, each new coating stage adds additional complexity and can modify the overall release profile of the drug.
Indeed, this latter problem is common to tablets as well. While much care may be taken in ensuring that the microencapsulated drug will release at a certain rate, placing sufficient material into a hard tablet for ingestion can change the release profile. It will take some time for the body to sufficiently digest the tablet and allow it to decompose or disintegrate into its component parts thereby releasing the microcapsules or microparticles. This adds an additional variable to the release profile and complicates formulation significantly.
One method of addressing these complications is by the provision of in-mouth, rapidly disintegrable tablets. These tablets will disintegrate in the mouth and release the microcapsules or microparticles which can then be swallowed. In essence, the tablet is useful for conveying the microencapsulated materials to the body. However, it disintegrates sufficiently rapidly such that it will not become an impediment or a significant factor in the overall release profile. By the use of this technology, ideally the release rate and profile of the drug would be identical to that of a standard tablet which is ingested or to that of an equivalent amount of microparticles which are swallowed.
Nonetheless, there is considerable room for improvement. Sustained-release or extended-release microcapsules and microparticles tend to be relatively larger and are often relatively hard. If an in-mouth delivery system is used, these particles are then released into the mouth and produce a sandy or gritty feel. This feel is exacerbated by large quantities of microencapsulated materials and/or the inclusion of relatively larger, tactily more significant, particles. It is an aim of the invention to address this problem.
Other problems are encountered in the formulation of prompt release, orally disintegrable tablets, especially those containing taste masked drug substances. These problems include xe2x80x9clocal accumulation.xe2x80x9d Upon disintegration in the mouth, local accumulations of powder may occur which are not immediately swallowed. Powder may adhere to various parts of the oral cavity such as the tongue, mucus membranes and between the teeth. These local accumulations of powder may have an unpleasant mouth fee. Moreover, if the dosage form contains unpleasant tasting drug particles which are taste masked by means of coating, adherence in the oral cavity allows a greater opportunity for dissolution of the coating and, hence, release of the drug into the oral cavity. The dissolved drug diffuses through the saliva to reach the taste buds, resulting in the patient experiencing an unpleasant taste.
The present invention solves these problems by, in one aspect, providing an orally disintegrable tablet suitable for use in the delivery of sustained or extended release formulations of coated granules, coated particles or microcapsules.
Applicants have found that a method of addressing the distasteful sensation which may accompany the use of extended or sustained release coated formulations is by providing a material which will decompose or disintegrate in the mouth so as to form a relatively viscous slurry with saliva. This viscous saliva slurry will help contain the particles as a loose but cohesive mass thereby preventing the particles from distributing throughout the mouth, i.e., under the tongue, between the gums and lips, etc. This therefore provides a greatly enhanced organoleptic sensation. This is accomplished by providing an in-mouth disintegrable formulation (orally disintegrating tablets, capsules, etc.) that includes an in-mouth viscosity enhancer which provides a pleasant mouth feel and helps to cause the individual particles to associate with each other and with saliva to thereby incorporate the extended release particles into a salivary mass of increased viscosity. This in turn allows the particles to stay together and glide smoothly and be easily swallowed. This in-mouth viscosity enhancing material can be, for example, an in situ formed gel or a material such as gums or various polymers. Mixtures are also contemplated.
The tablet preferably contains between about 10 and about 80% of an extended release coated material by weight of the tablet. For convenience, we will refer herein to these coated materials as xe2x80x9cmicrocapsules.xe2x80x9d However, it should be understood that this term contemplates the use of any extended, enteric or sustained-release vehicle, including microgranules, granules, microcapsules, particles, microparticles, adsorbates and the like known in the industry. Indeed, these particulate materials, referred to collectively herein as xe2x80x9cmicrocapsules,xe2x80x9d need not necessarily be coated at all; so long as they can achieve an extended release. These microcapsules generally have a particle size ranging from between about 50 to about 3,000 microns and include between about 5 and about 70% of a coating based on the weight of the microcapsules. The coating is an extended or enteric release coating.
The tablet also generally includes between about 5 and about 60% of a rapidly dissolvable sugar or sugar alcohol filler. The rapidly dissolvable sugar or sugar alcohol filler has a particle size selected to be complementary to the particle size of the microcapsules and generally ranges between about 300 and about 1,500 microns. The tablet also includes between about 0 and about 35% of a binder, including insoluble filler-binders, between about 1 and about 40% of a disintegrant; and between about 0 and about 50% of an effervescent couple. The sugar or sugar alcohol, binder disintegrant and if present, the effervescent couple are all provided in amounts based on the weight of the finished tablet.
By the use of the present invention one can develop in-mouth disintegrable tablets which can disintegrate in the mouth in under a minute, preferably under 30 seconds. The thus disintegrated tablet releases the sustained or extended release microcapsules into the mouth. The use of the viscosity enhancer helps to maintain the available saliva, excipients and microparticles as an integral mass. However, the resulting slurry remains both easy and pleasurable to swallow.
The present invention therefore solves the problems facing the prior art. Even with relatively large microcapsules, it is possible to obtain a dosage form which can disintegrate rapidly in the mouth and yet results in a pleasant organoleptic mouth feel. Relatively large microcapsules can be released into the mouth without a significant amount of chewing which could break the microcapsules and/or alter their release profile. The microcapsules are bound together, in a loose confederation, which reduces this tendency to dissipate throughout the mouth of the patient causing irritation, discomfort, and an adverse organoleptic sensation. Ideally, the pharmoco-kinetic performance of the drug administered through this dosage form will not be in any way altered by a comparison of the direct administration of equal amounts of non-tableted extended release microcapsules. Again, these increased organoleptic properties, coupled with the convenience of rapid and in-mouth disintegration, greatly assists in assuring compliance.
In another aspect of the present invention, closely related to that just described, the present invention provides a slurry generated in the mouth of a patient following the placement of a dosage form in the patient""s mouth to serve as a binding medium to hold certain non-extended release/non-enteric coated active ingredients together as a mass which can easily be swallowed. This decreases the opportunity for the particles or powders to stick to membranes or between teeth, leaving an unpleasant mouth feel and/or unpleasant taste. Moreover, to the extent that any coated or encapsulated drug was to permeate the coating, it would encounter a viscous salivary mixture through which the dissolved drug must diffuse in order to reach the taste buds. Since diffusion through the viscous medium is slow, little, if any, of the drug is tasted before it is swallowed. These various mechanisms improve the organoleptic properties of the medication. Of course, the use of both the extended release microcapsules and powders in a single dosage form are also contemplated. This would provide both an immediate release of drug and prolonged release as well.
It will be appreciated that the term xe2x80x9cpowderxe2x80x9d as used herein contemplates both a true powder, as well as truly crystalline materials, microgranulated and granulated materials, agglomerates, adsorbates and the like. In addition, when these powders are coated, the coating contemplated is a rapid release coatingxe2x80x94one which can assist in providing effective taste masking while providing minimal inference with the coated active ingredient""s normal dissolution profile. Ideally these coatings will dissolve, disintegrate or become sufficiently porous to allow the full release and dissolution of the coated drug in a manner consistent with the administration of the same drug in a completely uncoated fashion. Certainly, the use of these xe2x80x9ccoated powdersxe2x80x9d should not alter the dissolution rates of the drug in the digestive tract by more than an hour and preferably by less than half an hour.
In this way, these powder materials are distinguished from xe2x80x9cmicrocapsulesxe2x80x9d having extended, sustained, or enteric coatings as discussed herein. For convenience, these coated and uncoated species will be encompassed within the term xe2x80x9cpowder.xe2x80x9d
Furthermore, while the various aspects of the present invention will principally be described in terms of the use of microcapsules i.e., extended, enteric or sustained release species, the formulations described are applicable to both microcapsules and powders unless noted otherwise. Therefore, for example, in a particular formulation, an equivalent amount of a powder can be substituted for an equivalent amount of microcapsules. Of course, some adjustments may be necessary to account for the relative differences in the weight of the coatings used. However, the amount of uncoated drug should be equivalent in each case.
Another aspect of the present invention is the discovery of an interesting synergy which exists by the use of effervescent materials in combination with the dosage forms described herein. In addition to the normal role of effervescence in stimulating the mouth""s production of saliva, speeding disintegration, the aiding in taste masking, the presence of effervescence in the dosage forms of the present invention actually enhances the overall performance of these dosage forms. It is believed that effervescence helps provide a driving force and a mixing action which increases the speed with which the viscosity of the resulting slurry is formed. The effervescence also is believed to help carry the slurry away from the dissolving and disintegrating surface of the tablet such that the viscous slurry does not completely encapsulate same and retard further disintegration. Not a great deal of effervescence is required to obtain these results although the organoleptic properties of the dosage forms can be significantly altered based on the amount of effervescent material present.
In accordance with the present invention, xe2x80x9corally disintegrablexe2x80x9d means that the tablet will disintegrate substantially into its component parts (e.g. the powder, microcapsules and insoluble excipients, etc.) within three minutes, preferably within two minutes or less and more preferably within about one minute or less. For very large tablets, i.e., 2,500 mg or above, greater than three may be required. However, such extended disintegration time is contemplated in the phrase xe2x80x9csubstantially disintegrated.xe2x80x9d xe2x80x9cDissolvablexe2x80x9d or xe2x80x9cdissolution,xe2x80x9d in accordance with the present invention, refers to certain components of the tablet of the present invention which are substantially soluble in water and saliva. At least about 50% by weight of such ingredients will dissolve and preferably within about 90 seconds of a tablet being placed in a patient""s mouth.
Microcapsules in accordance with the present invention, includes active ingredients which are in the form of coated particles, microparticles, microcapsules, granules, microgranules, adsorbates, etc. and are provided in an amount of between about 10 and about 80% based on the tablet""s weight. This means that between 10 and 80% of the weight of the finished tablet is made up of microcapsules. More preferably, the amount of microcapsules ranges from between about 20-70% by weight.
These microcapsules should have a particle size ranging from between about 50 to about 3,000 microns, and more preferably between about 300 to about 2,000 microns.
Of these microcapsules, between about 5 to about 70% by weight of the microcapsules themselves is made up of the enteric, sustained release or extended release coating. Preferably, the amount of coating, by weight of the microcapsules, ranges from between about 10 to about 40% and more preferably from between about 10 to about 20%.
The coating in accordance with the present invention is an extended or enteric release coating. By extended or enteric release it is understood that while the microcapsules are rapidly dispersed in the mouth the active ingredients or drug itself is released from the microcapsules slowly or in a manner that alters its otherwise normal release profile. By the use of these coatings, the time necessary between doses of drug can be extended relative to the use of the same quantity of uncoated particles or microcapsules. Preferably the extended release coatings in accordance with the present invention will provide for a release of drug, with as uniform a rate as possible, over a period of time ranging from between about 4 to about 48 hours and more preferably from between about 4 to about 24 hours.
Preferred extended release coatings in accordance with the present invention include, for example, cellulose ethers, cellulose esters, polymethacrylates and copolymers, polyvinylacetate copolymers. Cellulose ethers include hydroxy-propylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose. Cellulose esters include hydroxypropylmethyl cellulose phthalate, cellulose-acetate phthalate, and hydroxypropylmethyl cellulose acetate succinate. Polymethacrylates include methacrylic acid/methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers and dimethyl amino-methyl methacrylate copolymers. Polyvinyl acetate copolymers include vinylacetate/vinylpyrrolidone copolymers polyvinylacetate phthalate and polyvinylpyrrolidone. Enteric coatings include, without limitation, cellulose acetate phthalate, shellac, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and a family of polymers sold under the trademark EUDRAGIT(copyright).
The active ingredient can include pharmaceutical ingredients, vitamins, minerals and dietary supplements. Pharmaceutical ingredients may include, without limitation, antacids, analgesics, anti-inflammatories, antipyretics antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, anti-flatuents, antimigraine agents, biologicals (proteins, peptides, oligonueleotides, etc.) anti-spasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers and combinations thereof. Also encompassed by the terms xe2x80x9cactive ingredient(s),xe2x80x9d xe2x80x9cpharmaceutical ingredient(s)xe2x80x9d and xe2x80x9cactive agentsxe2x80x9d are the drugs and pharmaceutically active ingredients described in Mantelle, U.S. Pat. No. 5,234,957, in columns 18 through 21. That text of Mantelle is hereby incorporated by reference.
As used in this disclosure, the term xe2x80x9cvitaminxe2x80x9d refers to trace organic substances that are required in the diet. For the purposes of the present invention, the term xe2x80x9cvitamin(s)xe2x80x9d includes, without limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E and vitamin K. Also included within the term xe2x80x9cvitaminxe2x80x9d are the coenzymes thereof. Coenzymes are specific chemical forms of vitamins. Coenzymes include thiamine pyrophosphates (TPP), flavin mononucleotide (FMM), flavin adenine dinucleotide (FAD), Nicotinamide adenine dinucleotide (NAD), Nicotinamide adenine dinucleotide phosphate (NADP), Coenzyme A (CoA), pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoyllysine, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term xe2x80x9cvitamin(s)xe2x80x9d also includes choline, carnitine, and alpha, beta, and gamma carotenes.
The term xe2x80x9cmineralxe2x80x9d refers to inorganic substances, metals, and the like required in the human diet. Thus, the term xe2x80x9cmineralxe2x80x9d as used herein includes, without limitation, calcium, (calcium carbonate), iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium and the like, and mixtures thereof. The term xe2x80x9cdietary supplementxe2x80x9d as used herein means a substance which has an appreciable nutritional effect when administered in small amounts. Dietary supplements include, without limitation, such ingredients as bee pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino-acids, proteins and mixtures thereof. As will be appreciated, dietary supplements may incorporate vitamins and minerals.
In general, the amount of active ingredient incorporated in each tablet or dosage form may be selected according to known principles of pharmacy. An effective amount of pharmaceutical ingredient is specifically contemplated. By the term xe2x80x9ceffective amount,xe2x80x9d it is understood that, with respect, to for example, pharmaceuticals, a xe2x80x9cpharmaceutically effective amountxe2x80x9d is contemplated. A xe2x80x9cpharmaceutically effective amountxe2x80x9d is the amount or quantity of a drug or pharmaceutically active substance which is sufficient to elicit the required or desired therapeutic response, or in other words, the amount which is sufficient to elicit an appreciable biological response when administered to a patient. As used with reference to a vitamin or mineral, the term xe2x80x9ceffective amountxe2x80x9d means an amount at least about 10% of the United States Recommended Daily Allowance (xe2x80x9cRDAxe2x80x9d) of that particular ingredient for a patient. For example, if an intended ingredient is vitamin C, then an effective amount of vitamin C would include an amount of vitamin C sufficient to provide 10% or more of the RDA. Typically, where the tablet includes a mineral or vitamin, it will incorporate higher amounts, preferably about 100% or more of the applicable RDA.
The amount of active ingredient used can vary greatly. Of course, the size of the dosage form, the requirements of other ingredients, and the number of, for example, tablets which constitute a single dose will all impact the upper limit on the amount of pharmacologically active ingredient which can be used. However, generally, the active ingredient is provided in an amount of between greater than zero and about 80% by weight of the finished tablet and, more preferably, in a range of between greater than zero and about 60% by weight thereof. Put in other terms, the active ingredient can be included in an amount of between about 1 microgram to about 2 grams, and more preferably between about 0.01 and about 1000 milligrams per dosage form, i.e., per tablet.
Dosage forms in accordance with the present invention also includes between about 5 and about 60% of a rapidly dissolvable sugar or sugar alcohol filler. This amount is based on the weight of the finished tablet. More preferably, the amount of such filler will range from between about 10 to about 35% by weight based on the tablet.
Rapidly dissolvable sugar and sugar alcohol in accordance with the present invention include, for example, mannitol, lactose, sucrose, maltose, dextrose, sorbitol, xylitol, maltitol, lactitol, and maltodextrins. Mannitol and other similar compounds having a negative heat of solution are preferred because they provide a particularly pleasant sensation enhancing the organoleptic experience of taking the tablet of the present invention. Most preferably, the filler is sucrose, mannitol, xylitol, lactose and maltose. When used at all, preferably only rapidly water soluble filler materials should be used.
Where necessary, granulated materials are used such that the particle size of the filler is complementary to that of the particle size of the microcapsules. xe2x80x9cComplementaryxe2x80x9d does not mean that the particle sizes need be exactly the same. However, the greater the degree of similarity, the greater the homogeneity of the material. The greater homogeneity, in turn, results in much greater uniformity of disintegration and dissolution. The particle size of the filler should therefore range from between about 100 to about 2,800 and more preferably between about 150 to about 1,500 microns.
For tableting purposes, a binder is preferred. The binder should be present in an amount of between about 0 to about 35% by weight based on the weight of the tablet. Preferably, the binder will be present in an amount which is greater than zero and indeed, in an amount of between about 3 to about 15%. Water soluble binders are preferred. But generally, such binders are water insoluble. Therefore, the effort should be made to minimize the content of such binders as the higher the overall content of insoluble materials such as the coated active, the lower the overall organoleptic quality of the formulation. Certain binders such as a number of insoluble filler-binders including microcrystalline cellulose sold under the trade name xe2x80x9cAVICELxe2x80x9d have additional advantageous properties that, despite their insolubility, make them nonetheless more desirable than other similar binders. A number of AVICEL formulations such as, for example, type PH113 available from FMC Corporation, Princeton, N.J. can act as a dry binder. However, when placed in an aqueous environment such as, in a patient""s mouth, the binder can actually aid in the disintegration of the tablet. In addition, microcrystalline cellulose imparts an almost creamy mouth feel which helps offset the negative impact of its insolubility. The use of such binders therefore helps reduce the overall amount of disintegrant which needs be used. Other binders include alginic acid, sodium alginate, starch, modified starches and other water swellable binders. Methyl cellulose is also preferred. Note that certain binders can also be used and classified as disintegrants as is known in the industry.
Other disintegrants are also often desirable.
Disintegrants, such as crospovidone (cross-linked polyvinyl pyrrolidone (cross-linked xe2x80x9cPVPxe2x80x9d)) are generally water insoluble. While they add to the rapid disintegration of the formulation, their inclusion can also add to the total content of insoluble ingredients making it more difficult to strike a balance between disintegration/dissolution speed and the resulting organoleptic sensation. Preferably, the amount of disintegrant will range from between greater than zero, i.e., about 1 to about 40% by weight based on the weight of the tablet and more preferably between about 3 to about 20%. Other disintegrants useful include sodium starch glycolate, croscarmallose sodium, microcrystalline cellulose and starch.
An effervescent couple is also preferred for use in accordance with the present invention. When present at all, it can be provided in a relatively small amount. The effervescent couple provides a number of advantages in the overall context of the present formulation. First, it aids in the disintegration of the tablet making it easier for the dissolvable constituents to dissolve and rapidly create a slurry. The presence of effervescence can also help stimulate the generation of saliva again facilitating disintegration, dissolution and the formation of an in-mouth slurry. Finally, many find the sensation of a mild amount of effervescence to be pleasing and this helps facilitate compliance by enhancing the organoleptic properties of the tablet.
The term effervescent couple(s) includes compounds which evolve gas. The preferred effervescent couples evolve gas by means of chemical reactions which take place upon exposure of the effervescent couple to water and/or to saliva in the mouth. The bubble or gas generating reaction is most often the result of the reaction of a soluble acid source and alkali metal carbonate or carbonate source. The reaction of these two general classes of compounds produces carbon dioxide gas upon contact with water included in saliva.
Such water activated materials should be kept in a generally anhydrous state with little or no absorbed moisture or in a stable hydrated form since exposure to water will prematurely disintegrate the tablet. The acid sources or acid may generally include food acids, acid anhydrides and acid salts. Food acids include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid and succinic acids, etc. Because these acids are directly ingested, their overall solubility in water is less important than it would be if the effervescent tablet formulations of the present invention were intended to be dissolved in a glass of water. Acids, anhydrides and salts may be used. Salts may include sodium, dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate salts and sodium acid sulfite.
Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate.
The effervescent couple of the present invention is not always based upon a reaction which forms carbon dioxide. Reactants which evolve oxygen or other gases which are safe are also considered within the scope. Where the effervescent couple includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, an equivalent ratio of components which provides for equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate base, or an equal amount of a di-reactive base should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either acid or carbonate source may exceed the amount of the other component. This may be useful to enhance taste and/or performance of a tablet containing an overage of either component. In this case, it is acceptable that the additional amount of either component may remain unreacted. It may be desirable to add an excess of one component in order that the excess may react with an in situ gel forming substance. An example of this is an excess of sodium bicarbonate to react with alginic acid to form a gel.
In general, the effervescent couple may be provided in an amount of between greater than zero to about 50% by weight of the tablet. More preferably, it will be provided in an amount of greater than zero to about 35%. It is preferred, however, that the effervescent couple be provided in an amount which is greater than zero. Indeed, while neither a binder nor an effervescent couple is required to provide acceptable performance, the use of at least one of a binder and/or effervescent couple is preferred. Most preferably, some amount of both are provided. An effervescent couple may not be needed when certain in-mouth viscosity enhancers are used. In other instances, the liberated gas in conjunction with the viscosity enhancer results in a slurry of the required viscosity.
The in-mouth viscosity enhancer or viscosity modifiers in accordance with the present invention can include gels, in-situ gel formers, gums and polymeric materials. The in-mouth viscosity enhancing material may include, for example, in-situ gel formers such as alginic acid and a complimentary soluble metal carbonate, a gum such as arabic, xanthan, guar, etc. and carbopolymers such as carbopols available from Croda, Inc., hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. Most preferred are methylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carbolpol and silicon dioxide. These materials are provided in an amount which is sufficient to increase the viscosity of the slurry that results from the disintegration and dissolution of the various other components of the tablet in a patient""s mouth. However, the amount of such in-mouth viscosity enhancing ingredients must be controlled to ensure that an organoleptically acceptable slurry results and that the increased viscosity does not too adversely affect either the in-mouth disintegration time or the organoleptic properties of the formulation.
The amount of these viscosity enhancers used to provide sufficient cohesion and form an organoleptically acceptable (i.e. one which is palatable and preferably pleasant) slurry will vary greatly depending upon a number of factors including the volume of medicine to be delivered, the type of patient (the viscosity may need to be different for children than for adults) the disintegration time and the specific type of viscosity enhancer used. The amount used will be that which provides an effective amount of viscosity to the slurry resulting from the disintegration of the dosage form, the dissolution of the saliva dissolvable species and the release of the insoluble species. Generally, the amount of viscosity enhancer will range from between about 1 and about 36% by weight and more preferably between about 2 and about 20%. In any event, sufficient viscosity enhancers should be used to provide effective viscosity enhancement. This means that the resulting viscosity of the slurry should range from between 25,000 to 500,000 (centipoise) CPS and more preferably between about 25,000 and about 300,000 CPS.
A lesser amount of a gum, for example, may be necessary than the amount of components necessary for the in-situ formation of a gel. It may also be necessary to include the varying proportions of viscosity modifiers. Thus, for example, if an alginic acid based gel is desirable, a greater proportion of a soluble metal carbonate may be necessary as compared to the amount of alginic acid provided. Between about 1 to about 35% by weight of the tablet may be alginic acid and a stoichiometric amount, or an excess, of a carbonate radical precursor may be desirable.
The metal carbonate is, preferably, a carbonate or bicarbonate of an alkali or alkaline earth metal, such as the metal sodium, potassium, calcium, magnesium or manganese. While aliginic acid is specifically mentioned, other in-situ gel forming acids may also be used so long as gel formation can be rapid, sufficient viscosity can be achieved and both the precursor and the resulting gel is pharmaceutically acceptable. See U.S. Pat. No. 4,414,198 which is hereby incorporated by reference and also a copy of which is attached. The slurry that results from the disintegration of the dosage form and exposure of the in-mouth viscosity enhancer to saliva should begin to provide sufficient viscosity to result in cohesion and an acceptable organoleptic sensation within about a minute or less of placing the dosage form in a patient""s mouth.
It will be appreciated that the disintegration of the dosage form, dissolution of selected excipients and formation of a viscous slurry does not necessarily happen all at once. As a tablet is placed in the mouth, its outer layer is exposed to saliva. AS the dissolvable materials dissolve and the tablet begins to disintegrate, microcapsules and/or powders are released and the viscosity enhancer begins to exert its influence helping mitigate the spread of the released drug and insoluble ingredients throughout the mouth. If a patient were to swallow while retaining the remainder of the dissolving tablet in their mouth, a more cohesive mass of material will be swallowed while the tablet continues its progression towards complete disintegration. Of course, the tablet material can be held completely in the mouth, without swallowing, in which case a more complete integral mass may eventually be swallowed. As each successive surface portion of the tablet is exposed to saliva, the available pool of viscous material is increased unless carried to another part of the mouth or swallowed.
This process can be greatly assisted by the presence of an effervescent material. The liberating gas helps to xe2x80x9cstir things upxe2x80x9d assisting in the stimulation of saliva necessary for the viscosity enhancers to be effective. They also help insure proper mixing of the viscosity enhancer with the saliva and other ingredients shortening the time necessary for the viscosity enhancing material to exert its influence.
Other common excipients such as, tableting lubricants, colors, sweeteners, flavors and the like may also be included. Lubricants, such as magnesium stearate should also be included in an amount of less than about 5% by weight of the finished tablet, preferably less than about 2% and most preferably about 0.5% by weight. The same is true for other excipients.
As previously noted, an equivalent amount of powder may be used in place of microcapsules. If the powder used is uncoated, then the amount of powder utilized is equal to the amount of active ingredient in encapsulated form used in the formulation as previously described. Therefore, if a tablet was to contain 70% coated acetaminophen and the acetaminophen was to be coated with an extended release coating that made up 20% by weight of the total weight of the microcapsule, then the amount of acetaminophen powder used would be equal to the amount of acetaminophen exclusive of the coating. In this example, the resulting amount of powder will make up a smaller percentage by weight of the total formulation, although the amount of acetaminophen administered in each instance is about the same.
If the acetaminophen powder was coated for taste masking purposes, then the amount of powder substituted for microcapsules in the formulation would also fall within the ranges previously described with a certain percentage of the powder being coating material as described herein. Any coating useful for taste masking, without significantly affecting the drug""s dissolution properties may be used. Preferred coatings include Opadry (Colorcon), Surelease (Colorcon), Aquacoat (FMC) and Eudragit (Rohm). Combinations and multiple layers such as a coating of Eudragit E100 is used in one layer and Surelease and Opadry are mixed to form a second layer are also contemplated.
Tablets according to the present invention can be manufactured by well-known tableting procedures. In common tableting processes, material which is to be tableted is deposited into a cavity, and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon compressive force is applied. The material is thus forced into conformity with the shape of the punches and the cavity. Hundreds, and even thousands, of tablets per minute can be produced in this fashion. Various tableting methods, well known to those skilled in the art, are comprehensively discussed throughout Pharmaceutical Dosage Forms: Tablets, Second Edition, edited by Herbert A. Lieberman et al., Copyright 1989 by Marcel Dekker, Inc., incorporated by reference herein, as well as other well known texts. Tablets should be compressed to a hardness of between about 10 and about 50 Newtons and preferably, about 15 to about 40 Newtons.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Orally disintegrable tablet forming a viscous slurry


An implantable sensor for use in the detection of quantitative measurement of an analyte in subcutaneous fluid, the sensor being biodegradable or hydrolysable in vivo. The sensor incorporates an assay for the analyte, the readout of which is a detectable or measurable optical signal which can, when the sensor is in operation in a subcutaneous location, be interrogated transcutaneously by external optical means.

The present invention relates to a sensor for use in the measurement or monitoring of analytes in subcutaneous fluid using optical techniques and to an analyte monitoring system using this sensor. The sensor is particularly suitable for use in situations in which analyte levels must be closely monitored, for example with drugs that must be maintained within a narrow therapeutic window or where analyte measurements must be taken repeatedly, such as in long term diabetes.
In the management of diabetes, the regular measurement of glucose in the blood is essential in order to ensure correct insulin dosing. Furthermore, it has been demonstrated that in the long term care of the diabetic patient better control of blood glucose levels can delay, if not prevent, the onset of retinopathy, circulatory problems and other degenerative diseases often associated with diabetes. Thus there is a need for reliable and accurate self-monitoring of blood glucose levels by diabetic patients.
Currently, blood glucose is monitored by diabetic patients with the use of commercially available colorimetric test strips or electrochemical biosensors (e.g. enzyme electrodes), both of which require the regular use of a lancet-type instrument to withdraw a suitable amount of blood each time a measurement is made. On average, the majority of diabetic patients would use such instruments to take a measurement of blood glucose twice a day. However, the US National Institutes of Health recently recommended that blood glucose testing should be carried out at least four times a day, a recommendation that has been endorsed by the American Diabetes Association. This increase in the frequency of blood glucose testing imposes a considerable burden on the diabetic patient, both in terms of financial cost and in terms of pain and discomfort, particularly in the long term diabetic who has to make regular use of a lancet to draw blood from the fingertips. Thus, there is clearly a need for a better long term glucose monitoring system that does not involve drawing blood from the patient.
There have been a number of recent proposals for glucose measurement techniques that do not require blood to be withdrawn from the patient. Various attempts have been made to construct devices in which an enzyme electrode biosensor is placed on the end of a needle or catheter which is inserted into a blood vessel (Wilkins E and Atanasov P, Med. Eng. Phys (1996) 18: 273-288). Whilst the sensing device itself is located within a blood vessel, the needle or catheter retains connection to the external environment. In practice, such devices are not suitable for use in human patients firstly because the insertion of a needle or catheter into a blood vessel poses an infection risk and is also uncomfortable for the patient and hence not suitable for continuous use. Secondly, devices of this type have not gained approval for use in human patients because it has been suggested that the device itself, on the end of a needle or catheter, may be responsible for the shedding of thromboses into the patient""s circulation. This obviously poses a very serious risk to the patient""s health.
Mansouri and Schultz (Biotechnology 1984), Meadows and Schultz (Anal. Chim. Acta. (1993) 280: pp 21-30) and U.S. Pat. No. 4,344,438 all describe devices for the in situ monitoring of low molecular weight compounds in the blood by optical means. These devices are designed to be inserted into a blood vessel or placed subcutaneously but require fibre-optic connection to an external light source and an external detector. Again the location of these devices in a blood vessel carries an associated risk of promoting thromboses and in addition, in one embodiment the need to retain a fibre-optic connection to the external environment is impractical for long term use and carries a risk of infection.
In the search for a less invasive glucose monitoring technique some attention has also been focused on the use of infra-red spectroscopy to directly measure blood glucose concentration in blood vessels in tissues such as the ear lobe or finger tip which are relatively xe2x80x98light transparentxe2x80x99 and have blood vessels sited close to the surface of the skin (Jaremko J and Rorstad O, Diabetes Care 1998 21:, 444-450 and Fogt E J, Clin. Chem. (1990) 36:, 1573-80) This approach is obviously minimally invasive, but has proven to be of little practical value due to the fact that the infra-red spectrum of glucose in blood is so similar to that of the surrounding tissue that in practical terms it is virtually impossible to resolve the two spectra.
It has been observed that the concentration of analytes in subcutaneous fluid correlates with the concentration of said analytes in the blood, consequently there have been several reports of the use of glucose monitoring devices which are sited in a subcutaneous location. In particular, Atanasov et al. (Med. Eng. Phys. (1996) 18: pp 632-640) describe the use of an implantable glucose sensing device (dimensions 5.0xc3x977.0xc3x971.5 cm) to monitor glucose in the subcutaneous fluid of a dog. The device consists of an amperometric glucose sensor, a miniature potentiostat, an FM signal transmitter and a power supply and can be interrogated remotely, via antenna and receiver linked to a computer-based data acquisition system, with no need for a connection to the external environment. However, the large dimensions of this device would obviously make it impractical for use in a human patient.
In WO 91/09312 a subcutaneous method and device is described that employs an affinity assay for glucose that is interrogated remotely by optical means. In WO 97/19188 a further example of an implantable assay system for glucose is described which produces an optical signal that can be read remotely. The devices described in WO 91/09312 and WO 97/19188 will persist in the body for extended periods after the assay chemistry has failed to operate correctly and this is a major disadvantage for chronic applications. Removal of the devices will require a surgical procedure.
There remains a clear need for sensitive and accurate blood glucose monitoring techniques which do not require the regular withdrawal of blood from the patient, which do not carry a risk of infection or discomfort and which do not suffer from the practical disadvantages of the previously described implantable devices.
Accordingly, in a first aspect the present invention provides a sensor for the detection or quantitative measurement of an analyte in subcutaneous fluid, the sensor being characterised in that it can function in a subcutaneous location with no physical connection to the external environment, said sensor incorporating an assay for said analyte the readout of which is a detectable or measurable optical signal, which optical signal can, when the sensor is in operation in a subcutaneous location, be interrogated transcutaneously by external optical means and said sensor being biodegradable or hydrolysable in vivo.
The sensor of the invention incorporates assay means for detecting an analyte or for measuring the amount of an analyte, the readout of the assay being an optical signal. Because the sensor is located just under the skin, an optical signal generated in the sensor can be detected transcutaneously (i.e. through the skin) thus obviating the need for any direct connection between the sensor and the external environment. Once the sensor is in place in a subcutaneous location analyte measurements can be taken as often as is necessary with no adverse effects. This is a particular advantage in relation to the long term care of diabetic patients because if glucose measurements are taken more frequently, tighter control can be maintained over the level of glucose in the blood and the risk of developing conditions related to poorly regulated blood glucose, such as retinopathy, arthritis and poor circulation, will be reduced.
Because the sensor of the invention does not itself contain any of the optical components required to interrogate the readout of the assay (these being provided separately and located outside the body) the sensor can easily be provided in a form which is injectable with minimal discomfort to the patient. In a preferred embodiment the components of the assay are incorporated into a matrix material which is permeable to subcutaneous fluid thereby allowing analytes such as glucose to enter the sensor by diffusion and to interact with the components of the assay. The matrix material may be an injectable formulation that forms a gel at the point of injection under the skin of the patient. Alternatively, the sensor may be formed from a solid polymeric matrix material incorporating the components of the assay which is again injected subcutaneously, the polymeric material being of a size suitable for injection through a narrow gauge needle to minimise the discomfort to the patient. When placed subcutaneously the solid polymeric material absorbs water and expands to form a gel thus hydrating the components of the assay.
The device of the present invention is biodegradable or hydrolysable in vivo. In operation, this sensor is placed in a subcutaneous location but then degrades slowly over a period of time. Once the sensor has degraded to an extent that it has ceased to be functionally effective in the monitoring of analytes a fresh sensor can be simply injected or implanted and there is no need for the old sensor to be surgically removed. For reasons of safety, it is desirable that the sensor should degrade into material which is completely eliminated from the body. In practice, this requires that the sensor degrade into materials capable of passing through human kidney membrane to be excreted in urine or which can be metabolised by the body.
As used herein the term xe2x80x98biodegradablexe2x80x99 should be taken to mean that the sensor device of the invention is degraded within the body into materials which can be substantially completely eliminated from the body leaving no residue and that once placed in the body the sensor of the invention becomes degraded to extent that it is substantially completely eliminated from the body within a reasonable timescale relative to the active life-span of the reactive components incorporated into the device. In other words, the sensor device of the invention should ideally be completely eliminated from the body shortly after it has ceased to be effective in accurately measuring/monitoring analyte. Thus, once the sensor ceases to be effective a fresh sensor can simply be put in place and the problem of accumulating old or spent devices within the body will be avoided. Preferably the sensor of the invention will become degraded such that it is substantially completely eliminated from the body over a period of less than one year, more preferably over a period of several months.
Materials suitable for the construction of such a biodegradable sensor include biodegradable block copolymers such as those described by Jeong et al., Nature 388: pp 860-862. Aqueous solutions of these materials are thermosensitive, exhibiting temperature-dependent reversible gel-sol transitions. The polymer material can be loaded with the components of the assay at an elevated temperature where the material forms a sol. In this form the material is injectable and on subcutaneous injection and subsequent rapid cooling to body temperature the material forms a gel matrix. The components of the assay are suspended within this gel matrix which thus constitutes a sensor suitable for detecting or measuring analytes in subcutaneous fluid. Low molecular weight analytes, such as glucose, can freely diffuse into the gel matrix from the surrounding subcutaneous fluid. This particular embodiment of the invention has the advantage that there is no requirement for a surgical procedure for implantation of the sensor. Subcutaneous injection of the sol phase material causes neither significant pain nor tissue damage.
As an alternative to the gel based sensor described above the sensor may be constructed from a solid or gel-like biodegradable polymer matrix material within which the assay components are distributed. When injected or implanted subcutaneously this solid polymer sensor hydrates, swells and analyte penetrates through the structure to encounter the assay components.
In a further embodiment the sensor may be constructed in the form of a hollow chamber, the walls of the chamber being constructed of solid biodegradable polymer material or of a soluble glass and defining a central space in which the components of the assay are contained Low molecular weight analytes are able to diffuse through the chamber walls or through a permeable end plug into the central space and thus come into contact with the components of the assay. The walls of the hollow chamber would gradually degrade over time.
Both the solid polymer sensors and the hollow chamber sensors may be introduced into a subcutaneous location by implantation or injection, injection being preferred for sensors with a diameter of less than 2 mm. Both types of sensors can be formed in a wide variety of geometric shapes as desired prior to injection or implantation, cylindrical sensors being particularly preferred.
Biodegradable materials suitable for use in the construction of the hollow chamber and solid polymer sensors include cross-linked proteins such as human albumin, fibrin gels, polysaccharides such as starch or agarose, poly (DL-lactide) and poly (DL-glycolide), polyanhydrides, fatty acid/cholesterol mixtures that form semi-solid derivates, hyaluronates and liquid crystals of monooliein and water.
In a still further embodiment, the sensor may be formed as a suspension of microparticles of preferred dimeter  less than 100 xcexcm each of which contains the assay components either encapsulated inside a hollow microparticle, or dispersed within the material of a solid microparticle. Such a suspension of microparticles is readily injected subcutaneously. Preferably the microparticles are formed from a material which is biodegradable or hydrolysable in vivo. Alternatively, liposomes containing the assay components can be used. Liposomes of diameter 0.3 to 2.0 xcexcm have been shown to remain at the site of injection (Jackson A J., Drug Metab. Dispos. 1981 9, 535-540) so they would be suitable for use in the sensor. In a further embodiment the sensor comprises a plurality of empty erythrocytes which have been loaded with assay components and then injected subcutaneously. Empty erythrocytes, also known as erythrocyte ghosts, can be prepared by exposing intact erythrocytes to a hypotonic solution so that they swell and burst to release their cytoplasmic contents. The empty erythrocytes can then be loaded with assay components before allowing the plasma membranes to re-seal.
In the preferred embodiments of the sensor (i.e. gel, solid polymer, hollow chamber, or microparticles) it is advantageous for the assay components to have a restricted diffusion in order to minimise their loss from the sensor. This can be achieved by ensuring that the gel or the biodegradable material has a pore size that permits the diffusion of low molecular weight analytes but not the assay components themselves. These would only be lost as the material or gel degrades over time. The assay components are preferably of high molecular weight, such as proteins or polymers, in order to restrict their loss from the sensor.
There are several different mechanisms by which a biodegradable sensor can be degraded into materials which can be eliminated from the body, including hydrolysis, dissolution and cleavage of susceptible bonds by enzymic action, including the action of components of the immune system. The mechanism of degradation is ultimately dependent on the nature of the material from which the sensor is constructed. For example, most biodegradable polymer materials, such as polylactides and polyglycolides, are hydrolysable by water. A sensor device comprising a matrix of hydrolysable polymer in which the reactive components of the assay are embedded therefore degrades as a result of hydrolysis of the matrix, gradually releasing the reactive components. The overall time taken for the matrix to degrade will generally be dependent on the concentration of polymer in the matrix material and on the overall dimensions of the sensor. Once released from the matrix material, the reactive components of the assay, being protein or carbohydrate based, are either taken up by the liver and thereby removed or broken down in situ by the action of enzymes.
Assays suitable for use in the sensor include reactions such as hydrolysis and oxidation leading to a detectable optical change i.e. fluorescence enhancement or quenching which can be observed transcutaneously. A preferred assay for use in the sensor of the invention is a binding assay, the readout of which is a detectable or measurable optical signal which can be interrogated transcutaneously using optical means. The binding assay generating the optical signal should preferably be reversible such that a continuous monitoring of fluctuating levels of the analyte can be achieved. This reversibility is a particular advantage of the use of a binding assay format in which the components of the assay are not consumed. Binding assays are also preferred for use in the sensor of the invention for reasons of safety as they cannot generate any unwanted products as might be generated by an enzymatic or electrochemical reaction.
Preferred binding assay configurations for use in the sensor of the invention include a reversible competitive, reagent limited, binding assay, the components of which include an analyte analog and an analyte binding agent capable of reversibly binding both the analyte of interest and the analyte analog. The analyte of interest and the analyte analog compete for binding to the same binding site on the analyte binding agent. Such competitive binding assay configurations are well known in the art of clinical diagnostics and are described, by way of example, in The Immunoassay Handbook, ed. David Wild, Macmillan Press 1994. Suitable analyte binding agents for use in the assay would include antibodies or antibody fragments which retain an analyte binding site (e.g. Fab fragments), lectins (e.g. concanavalin A), hormone receptors, drug receptors, aptamers and molecularly-imprinted polymers. Preferably the analyte analog should be a substance of higher molecular weight than the analyte such that it cannot freely diffuse out of the sensor. For example, an assay for glucose might employ a high molecular weight glucose polymer such as dextran as the analyte analog.
Suitable optical signals which can be used as an assay readout in accordance with the invention include any optical signal which can be generated by a proximity assay, such as those generated by fluorescence energy transfer, fluorescence polarisation, fluorescence quenching, phosphorescence techniques, luminescence enhancement, luminescence quenching, diffraction or plasmon resonance, all of which are known per se in the art.
The most preferred embodiment of the sensor of the invention incorporates a competitive, reagent limited binding assay which generates an optical readout using the technique of fluorescence energy transfer. In this assay format the analyte analog is labelled with a first chromophore (hereinafter referred to a the donor chromophore) and the analyte binding agent is labelled with a second chromophore (hereinafter referred to as the acceptor chromophore). It is an essential feature of the assay that the fluorescence emission spectrum of the donor chromophore overlaps with the absorption spectrum of the acceptor chromophore, such that when the donor and acceptor chromophores are brought into close proximity by the binding of the analyte analog to the analyte binding agent a proportion of the fluorescent signal emitted by the donor chromophore (following irradiation with incident radiation of a wavelength absorbed by the donor chromophore) will be absorbed by the proximal acceptor chromophore, a process known in the art as fluorescence energy transfer, with the result that a proportion of the fluorescent signal emitted by the donor chromophore is quenched and, in some instances, that the acceptor chromophore emits fluorescence. Fluorescence energy transfer will only occur when the donor and acceptor chromophores are brought into close proximity by the binding of analyte analog to analyte binding agent. Thus, in the presence of analyte, which competes with the analyte analog for binding to the analyte binding agent, the amount of quenching is reduced (resulting in a measurable increase in the intensity of the fluorescent signal emitted by the donor chromophore or a fall in the intensity of the signal emitted by the acceptor chromophore) as labelled analyte analog is displaced from binding to the analyte binding agent. The intensity of the fluorescent signal emitted from the donor chromophore thus correlates with the concentration of analyte in the subcutaneous fluid bathing the sensor.
An additional advantageous feature of the fluorescence energy transfer assay format arises from the fact that any fluorescent signal emitted by the acceptor chromophore following excitation with a beam of incident radiation at a wavelength within the absorption spectrum of the acceptor chromophore is unaffected by the fluorescence energy transfer process. It is therefore possible to use the intensity of the fluorescent signal emitted by the acceptor chromophore as an internal reference signal, for example in continuous calibration of the sensor or to monitor the extent to which the sensor has degraded and thus indicate the need to implant or inject a fresh sensor. As the sensor degrades, the amount of acceptor chromophore present in the sensor will decrease and hence the intensity of fluorescent signal detected upon excitation of the acceptor chromophore will also decrease. The fall of this signal below an acceptable baseline level would indicate the need to implant or inject a fresh sensor.
Competitive binding assays using the fluorescence energy transfer technique which are capable of being adapted for use in the sensor of the invention are known in the art. U.S. Pat. No. 3,996,345 describes immunoassays employing antibodies and fluorescence energy transfer between a fluorescer-quencher chromophoric pair. Meadows and Schultz (Anal. Chim. Acta (1993) 280: pp 21-30) describe a homogeneous assay method for the measurement of glucose based on fluorescence energy transfer between a labelled glucose analog (FITC labelled dextran) and a labelled glucose binding agent (rhodamine labelled concanavalin A). In all of these configurations the acceptor and donor chromophores/quenchers can be linked to either the binding agent or the analyte analog.
An alternative to the fluorescence energy transfer is the fluorescence quenching technique. In this case a compound with fluorescence quenching capability is used instead of the specific acceptor chromophore and the optical signal in a competitive binding assay will increase with increasing analyte. An example of a powerful and non-specific fluorescence quencher is given by Tyagi et al. Nature Biotechnology (1986) 18: p. 49.
The sensor of the invention can be adapted for the detection or quantitative measurement of any analyte present in subcutaneous fluid. Preferred analytes include glucose (in connection with the long-term monitoring of diabetics), urea (in connection with kidney disease or disfunction), lactate (in connection with assessment of muscle performance in sports medicine), ions such as sodium, calcium or potassium and therapeutic drugs whose concentration in the blood must be closely monitored, such as, for example, digoxin, theophylline or immunosuppressant drugs. The above analytes are listed by way of example only and it is to be understood that the precise nature of the analyte to be measured is not material to the invention.
The sensor is interrogated transcutaneously using optical means, i.e. no physical connection is required between the sensor and the optical means. When the sensor incorporates a competitive, reagent limited, binding assay employing the technique of fluorescent energy transfer, the optical means should supply a first beam of incident radiation at a wavelength within the absorption spectrum of the donor chromophore and preferably a second beam of incident radiation at a wavelength within the absorption spectrum of the acceptor chromophore. In addition, the optical means should be capable of measuring optical signals generated in the sensor at two different wavelengths; wavelength 1 within the emission spectrum of the donor chromophore (the signal generated in connection with the measurement of analyte and wavelength 2 in the emission spectrum of the acceptor chromophore (which could be the analyte signal or the internal reference or calibration signal).
Optical means suitable for use in remote interrogation of the device of the invention includes a simple high-throughput fluorimeter comprising an excitation light source such as, for example, a light-emitting diode (blue, green or red  greater than 1000 mCa), an excitation light filter (dichroic filter), a fluorescent light filter (dichroic or dye filter) and a fluorescent light detector (PIN diode configuration). A fluorimeter with these characteristics may exhibit a sensitivity of between picomolar to femtomolar fluorophore concentration.
A suitable fluorimeter set-up is shown in the accompanying FIG. 1 and described in the Examples included herein. The fluorimeter separately measures the following parameters:
At wavelength 1 (donor chromophore)
Excitation light intensity, I(1,0)
Ambient light intensity, I(1,1)
Intensity of combined fluorescent and ambient light, I(1,2)
At wavelength 2 (acceptor chromophore)
Excitation light intensity, I(2,0)
Ambient light intensity, I(2,1)
Intensity of combined fluorescent and ambient light, I(2,2)
Measurements are taken by holding the fluorimeter close to the skin and in alignment with the sensor. When making transcutaneous measurements of the fluorescent signals generated in the sensor it is necessary to take account of the absorption of signal by the skin, the absorptivity of human skin is found by experiment to be lowest in the range from 400 nm to 900 nm. The final output provided is the normalized ratio between the fluorescent intensity from the two fluorophores, defined by the following relation (Equation 1):
(I(1,2)xe2x88x92I(1,1)) I(2,0)
(I(2,2)xe2x88x92I(2,1)) I(1,0)xe2x80x83xe2x80x83(1)
In a third aspect the invention provides an analytical system suitable for the detection or quantitative measurement of an analyte in subcutaneous fluid, said analytical system comprising,
(i) a sensor for the detection or quantitative measurement of an analyte in subcutaneous fluid in accordance with the first aspect of the invention;
(ii) optical means suitable for the transcutaneous interrogation of the sensor of (i).
In a fourth aspect the invention provides a method of detecting or quantitatively measuring an analyte in the subcutaneous fluid of a mammal, which method comprises the steps of,
(a) injecting or implanting a sensor for the detection or quantitative measurement of an analyte in subcutaneous fluid in accordance with the first aspect of the invention;
(b) allowing the assay of said sensor to reach thermodynamic equilibrium;
(c) interrogating the readout of said assay using optical means; and
(d) relating the measurement obtaining in (c) to the concentration of analyte.
The final output from the optical means (e.g. the fluorimeter) as given by Equation 1 above is converted to analyte concentration preferably by means of a computer using calibration data which can be obtained based on the principles set out below.
A calibration curve can be established empirically by measuring response versus analyte concentration for a physiologically relevant range of analyte concentrations. Preferably this takes place in vitro as part of the production of the sensor device. The calibration procedure can be simplified considerably by using the mathematical relation between response and analyte concentration in a competitive affinity sensor which is derived as follows:
The response of a competitive affinity sensor is governed by the reactions:
RCxe2x88x92R+C
RLxe2x88x92R+L
designating the dissociation of the complexes RC and RL, formed by the combination of analyte binding agent (R) with analyte (L) or analyte analog (C).
The corresponding dissociation equilibrium constants are:                               K          1                =                                            C              R                                                  C              C                                            C            RC                                          and                                    K          2                =                                            C              R                                                  C              L                                            C            RL
where C designates the number of moles of the species in the sensor divided by the sensor volume. Using this measure of concentration both immobilized species and species in solution are treated alike.
The mass balance equations are:
TC=CC+CRC
for total analyte analog concentration and,
TR=CR+CRC+CRL
for total analyte binding agent concentration.
Using the expression above, the relation between response and analyte concentration is derived:                                                                         T                c                            -                              C                c                                                    C              c                                                      K            1                          =                                            T              R                        -                          (                                                T                  c                                -                                  C                  c                                            )                                            1            +                          (                                                C                  2                                /                                  K                  2                                            )                                                          (        2        )
By using this relation the amount of data necessary for the calibration can be reduced to two key parameters: Total analyte binding agent concentration and total analyte analog concentration. The calibration curve is thus determined by two points on the curve.

Optical sensor for in situ measurement of analytes


Methods, systems, and apparatus, including computer programs encoded on computer storage media can be used to facilitate information and access to accounts. One of the methods includes in response to determining that a user has reported a card associated with an account as lost or stolen, providing a user interface option to associate the account with a digital wallet. The method includes in response to receiving a request from a user associating the accord with the digital wallet absent associating a card associated with the account with the digital wallet.

Mobile banking is a service provided by a bank or other financial institution that allows its customers to conduct financial transactions remotely using a mobile device such as a smartphone or tablet. Unlike the related internet banking, it uses software, usually called an app, provided by the financial institution for the purpose. Mobile banking is usually available on a 24-hour basis. Some financial institutions have restrictions on which accounts may be accessed through mobile banking, as well as a limit on the amount that can be transacted.

Technical solutions to lost credit cards

United Services Automobile Association (USAA)